US4960937A - Process for the preparation of trans-1,1,2-triphenyl-but-1-ene derivatives - Google Patents
Process for the preparation of trans-1,1,2-triphenyl-but-1-ene derivatives Download PDFInfo
- Publication number
- US4960937A US4960937A US07/263,209 US26320988A US4960937A US 4960937 A US4960937 A US 4960937A US 26320988 A US26320988 A US 26320988A US 4960937 A US4960937 A US 4960937A
- Authority
- US
- United States
- Prior art keywords
- trans
- set forth
- phenyl
- parts
- triphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 8
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract 4
- 230000007717 exclusion Effects 0.000 claims abstract 2
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- 238000007796 conventional method Methods 0.000 claims 1
- 230000018044 dehydration Effects 0.000 abstract description 3
- 238000006297 dehydration reaction Methods 0.000 abstract description 3
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- JQKMNNYZQUQIJJ-UHFFFAOYSA-N 1,1-diphenylbut-1-en-2-ylbenzene Chemical class C=1C=CC=CC=1C(CC)=C(C=1C=CC=CC=1)C1=CC=CC=C1 JQKMNNYZQUQIJJ-UHFFFAOYSA-N 0.000 description 2
- VFFBJZCCXOYRNN-UHFFFAOYSA-N 1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenylbutan-1-ol Chemical compound C=1C=CC=CC=1C(O)(C=1C=CC(OCCN(C)C)=CC=1)C(CC)C1=CC=CC=C1 VFFBJZCCXOYRNN-UHFFFAOYSA-N 0.000 description 2
- BUKANFTWZXJIGD-UHFFFAOYSA-N 3-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-hydroxy-2-phenylbutyl]phenol Chemical compound C=1C=C(OCCN(C)C)C=CC=1C(O)(C=1C=C(O)C=CC=1)C(CC)C1=CC=CC=C1 BUKANFTWZXJIGD-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000005156 Dehydration Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- MPMAKJDYHJDJDO-UHFFFAOYSA-N 3-[1-[4-[2-(diethylamino)ethoxy]phenyl]-1-hydroxy-2-phenylbutyl]phenol Chemical compound C=1C=C(OCCN(CC)CC)C=CC=1C(O)(C=1C=C(O)C=CC=1)C(CC)C1=CC=CC=C1 MPMAKJDYHJDJDO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
Definitions
- the active ingredient 1-[4'-(2-dimethylaminoethoxy) phenyl]-trans-1,2-diphenyl-but-1-ene has entered into the therapy, and in the meantime has become known throughout the world by the designation TAMOXIFEN (INN).
- carbinols of the general formula 2 are transformed directly into the trans-olefins of formula 1 in the absence of organic solvents by the influence of hydrochloric acid or of sulphuric acid at increased temperature. Under these conditions, the formation of cis-olefins of formula 3 is practically suppressed.
- the conversion of the carbinols in accordance with formula 2 into the trans-olefins of formula 1 is carried out for preference in the temperature range from 50° to 60° C. Hydrochloric or sulphuric acid is permitted to take effect at increased temperature, preferably for from 12 to 16 hours, but at least for 10 hours.
Abstract
The invention concerns the direct preparation of trans-1,1,2-triphenyl-but-1-ene derivatives having the general formula 1 by dehydration of carbinols having the general formula 2 by heating in a strongly hydrochloric or sulphuric acid medium with the exclusion of organic solvents. ##STR1##
Description
In recent years a series of triphenylbutene derivatives has been described which are suitable because of their antioestrogic properties for the treatment of hormone-dependent mamma tumors (R. Sutherland and V.C. Jordan, "Nonsteroidal Antioestrogens" Academic Press, 1981).
The active ingredient 1-[4'-(2-dimethylaminoethoxy) phenyl]-trans-1,2-diphenyl-but-1-ene has entered into the therapy, and in the meantime has become known throughout the world by the designation TAMOXIFEN (INN).
When synthesising 1,1,2-triphenyl-but-1-ene derivatives, there accumulate in the dehydration stage of the diastereomeric carbinols of formula 2 the geometrically isomeric olefins of formulae 3 and 1 [cis/trans- or E/Z-form]in the mixture. ##STR2##
Because only the active isomer can be considered for clinical application, it was necessary to isolate the pure trans-form from the resulting isomer mixture. This was done until now by costly processes making heavy losses such as fractionated crystallization or by chromatography. [UK Pat. No. 1 013 907; U.S. Pat. No. 4,536,516; European Pat. No. 0 054 168; G. R. Bedford and D. N. Richardson, Nature 212, 733-734 (1966); P. Sohar et al., Acta Chim. Acad. Sci. Hung. 100, 69-74 (1979); D. W. Robertson and J. A. Katzenellenbogen J. Org. Chem. 47, 2387-2393 (1982); P. C. Ruenitz et al., J. Med. Chem. 25, 1056-1060 (1982); R. D. Armstrong, J. Chromatogr. 414, 192-196 (1987)].
The unsatisfactory yield of Tamoxifen could only be increased when it became possible to subject the previously worthless mother liquor fractions which are enriched with the cis-form to a conversion into the trans-form. As can be seen from European Pat. No. 0 127 128, the cis-form can be converted into the trans-form in a strongly hydrochloric acid milieu at increased temperature.
Surprisingly a substantial simplification in the process for the preparation of trans-1,1,2-triphenyl-but-1-ene derivatives of the general formula 1 has now become possible. As will be shown, carbinol compounds having the general formula 2 can under certain conditions be largely transformed in a single step into the trans-olefins having the general formula 1. Thereby the stages which were necessary in the previous preparation processes:
a) isolation of the cis/trans isomer mixture after dehydration of the diastereomeric carbinols,
b) separation of the trans-form by crystallization or by chromatography and
c) re-isomerization of the mother liquor fractions enriched with the cis-form can be omitted totally.
In the process according to the invention carbinols of the general formula 2 are transformed directly into the trans-olefins of formula 1 in the absence of organic solvents by the influence of hydrochloric acid or of sulphuric acid at increased temperature. Under these conditions, the formation of cis-olefins of formula 3 is practically suppressed.
The conversion of the carbinols in accordance with formula 2 into the trans-olefins of formula 1 is carried out for preference in the temperature range from 50° to 60° C. Hydrochloric or sulphuric acid is permitted to take effect at increased temperature, preferably for from 12 to 16 hours, but at least for 10 hours.
The invention will be explained in more detail on the basis of the examples of embodiments given below.
1 part of 1-[4'-(2-dimethylaminoethoxy)phenyl]-1,2-diphenyl-butane-1-ol is stirred in ten parts of 50 % by volume sulphuric acid, and the suspension is heated for 14 hours with intensive stirring to 55° C. Subsequently cooling is carried out and with the addition of 2.5 parts ice and 12.5 parts of concentrated ammonia, alkalization is performed. The reaction product is taken up in ethylacetate and the organic phase is washed repeatedly with water. After the removal of the organic solvent in the vacuum 0.9 parts of residue remain with a content of 1-[4'-(2-dimethylaminoethoxy)phenyl]-trans-1,2-diphenyl-but-1-ene of 94 % [HPLC]. Crystals from acetone have a melting point of 98° C. Content: 99.4 % [HPLC].
1 part of 1-[4'-(2-dimethylaminoethoxy)phenyl]-1,2-diphenyl-butane-1-ol is stirred in 6 parts of 32 % by weight hydrochloric acid and the suspension is heated for 16 hours with intensive stirring to 52° C. Subsequently cooling is performed and with the addition of 2 parts of ice and 6 parts of concentrated ammonia, alkalization is carried out. The reaction product is taken up in ethylacetate and the organic phase is washed repeatedly with water. After the removal of the organic solvent in the vacuum, 0.97 parts of residue remain with a content of 1-[4'-(2-dimethylaminoethoxy)phenyl]-trans-1,2-diphenyl- but-1-ene of 96 % [HPLC]. Crystals from methanol/water have a melting point of 96 to 98° C; content: 99.7 % [HPLC]
1 part of 1-[4'-(2-dimethylaminoethoxy)phenyl]-1(3'-hydroxyphenyl) - 2-phenyl-butane-1-ol is stirred in 9 parts of 50 % by volume sulphuric acid and the suspension is heated for 15 hours with intensive stirring to 52° C. Subsequently cooling is carried out and alkalization is performed with the addition of 3 parts of ice and 12 parts concentrated ammonia. The reaction product is taken up in dichloromethane and the organic phase is repeatedly washed with water. After the removal of the organic solvent in the vacuum 0.9 parts of residue remain with a content of 1-[4'-(2-dimethylaminoethoxy)-phenyl]-trans-1-(3'-hydroxyphenyl)-2-phenyl-but-1-ene of 90 % [HPLC]. Crystals from ethanol have a melting point of 164° C; content: 99.5 % [HPLC].
1 part 1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'-hydroxy- phenyl)-2-phenyl-butane-1-ol is stirred in 6 parts of 37 % by weight hydrochloric acid and the suspension is heated for 16 hours to 50° C with intensive stirring. Subsequently cooling is effected and alkalization is carried out with the addition of 3 parts of ice and 4 parts concentrated ammonia. The reaction product is taken up in dichloromethane and the organic phase is repeatedly washed with water. After the removal of the organic solvent in the vacuum 0.85 parts of residue remain with a content of 1-[4'-(2-dimethylaminoethoxy)-phenyl]-trans-1-(3'-hydroxy- phenyl)-2-phenyl-but-1-ene of 93 % [HPLC]. Crystals from ethanol have a melting point of 164° C; content: 99.6 % [HPLC].
1 part of 1-[4'-(2-diethylaminoethoxy)phenyl]-1-(3-hydroxyphenyl)-2-phenyl-butane-1-ol is stirred in 8 parts of 37 % by weight hydrochloric acid and the suspension is heated for 15 hours to 52° C with intensive stirring. Subsequently cooling is carried out and alkalization is performed with the addition of 4 parts of ice and 5 parts concentrated ammonia. The reaction product is taken up in dichloromethane and the organic phase is washed repeatedly with water. After the removal of the organic solvent in the vacuum 0.95 parts of residue remain with a content of 1-[4'-(2-diethylaminoethoxy)-phenyl]-trans-1-(3'-hydroxy- phenyl)-2-phenyl-but-1-ene of 95 % [HPLC]. Crystals from isopropanol have a melting point of130° C; content: 99.5 % [HPLC].
Claims (7)
1. A process for the preparation of trans-1,1,2-triphenyl-but-1-ene derivatives having the general formula 1 ##STR3## in which R1 ═CH3, CH2 CH3 and R2 ═H, OH, wherein carbinols having the general formula 2 ##STR4## in which R1 and R2 possess the meaning which is given in formula 1 are heated for 10-16 hours at a temperature of from 50°-60° C. in a strongly hydrochloric of sulphuric acid medium with the exclusion or organic solvents and wherein the reaction product is recovered by conventional methods.
2. A process as set forth in claim 1, wherein the hydrochloric acid concentration amounts to at least 25% by weight or wherein the sulphuric acid concentration is at least 40% by volume.
3. A process as set forth in claim 2, wherein said heating is carried out at a temperature of from 50°-55° C.
4. A process as set forth in claim 1, wherein said heating is carried out at a temperature of from 50°-55° C.
5. A process as set forth in claim 1, wherein the hydrochloric acid concentration is from 32-37% by weight.
6. A process as set forth in claim 1, wherein the sulphuric acid concentration is from 45-50% by volume.
7. A process as set forth in claim 1, wherein said heating is carried out from 12-16 hours at a temperature of from 50°-55° C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3736682 | 1987-10-29 | ||
| DE19873736682 DE3736682A1 (en) | 1987-10-29 | 1987-10-29 | METHOD FOR PRODUCING TRANS-1,1,2-TRIPHENYL-BUT-1-EN DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4960937A true US4960937A (en) | 1990-10-02 |
Family
ID=6339363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US07/263,209 Expired - Fee Related US4960937A (en) | 1987-10-29 | 1988-10-27 | Process for the preparation of trans-1,1,2-triphenyl-but-1-ene derivatives |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4960937A (en) |
| EP (1) | EP0313799B1 (en) |
| AT (1) | ATE85605T1 (en) |
| DE (2) | DE3736682A1 (en) |
| DK (1) | DK170300B1 (en) |
| ES (1) | ES2038263T3 (en) |
| FI (1) | FI94625C (en) |
| GR (1) | GR3007027T3 (en) |
| HU (1) | HU202824B (en) |
| NO (1) | NO169120C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5565611A (en) * | 1993-10-25 | 1996-10-15 | Taiho Pharmaceutical Co., Ltd. | Process for preparing acid addition salt of Z-isomer of triphenylethylene compound |
| US5681835A (en) * | 1994-04-25 | 1997-10-28 | Glaxo Wellcome Inc. | Non-steroidal ligands for the estrogen receptor |
| US5693863A (en) * | 1994-01-03 | 1997-12-02 | Klinge Pharma Gmbh | Method for the production of E-1- 4'- (2- Dimethylaminoethoxy) - Phenyl!-1-(3-Hydroxyphenyl) -2-Phenyl-1-Butene |
| US7307102B2 (en) | 1997-08-15 | 2007-12-11 | Duke University | Method of preventing or treating estrogen-dependent diseases and disorders |
| CN114133334A (en) * | 2021-11-09 | 2022-03-04 | 北京京丰制药(山东)有限公司 | Industrial preparation process of tamoxifen citrate |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU725286B2 (en) | 1996-01-20 | 2000-10-12 | Bradford University | Tamoxifen and analogues thereof |
| GB9715479D0 (en) * | 1997-07-23 | 1997-10-01 | Univ Bradford | Tamoxifen and analogues thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1013907A (en) * | 1962-09-13 | 1965-12-22 | Ici Ltd | Alkene derivatives |
| EP0127128A1 (en) * | 1983-05-24 | 1984-12-05 | Bristol-Myers Company | Process for the conversion of the E isomer of 1,2-diphenyl-1-(4-(2-dimethylaminoethoxy)-phenyl)-1-butene to tamoxifen HCl |
| US4536516A (en) * | 1962-09-13 | 1985-08-20 | Imperial Chemical Industries Plc | Alkene derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3046719C2 (en) * | 1980-12-11 | 1983-02-17 | Klinge Pharma GmbH, 8000 München | 1,1,2-Triphenyl-but-1-ene derivatives, processes for their preparation and pharmaceuticals |
| GB2160202B (en) * | 1984-06-12 | 1987-12-02 | Nat Res Dev | Preparation of tamoxifen |
| CN1013859B (en) * | 1986-11-21 | 1991-09-11 | 中国人民解放军防化研究院第四所 | Improvements for synthesis of citric acid triphenylamine oxide |
-
1987
- 1987-10-29 DE DE19873736682 patent/DE3736682A1/en not_active Withdrawn
-
1988
- 1988-09-19 EP EP88115306A patent/EP0313799B1/en not_active Expired - Lifetime
- 1988-09-19 AT AT88115306T patent/ATE85605T1/en not_active IP Right Cessation
- 1988-09-19 DE DE8888115306T patent/DE3878394D1/en not_active Expired - Fee Related
- 1988-09-19 ES ES198888115306T patent/ES2038263T3/en not_active Expired - Lifetime
- 1988-09-28 FI FI884461A patent/FI94625C/en not_active IP Right Cessation
- 1988-10-27 NO NO884800A patent/NO169120C/en not_active IP Right Cessation
- 1988-10-27 US US07/263,209 patent/US4960937A/en not_active Expired - Fee Related
- 1988-10-28 DK DK604288A patent/DK170300B1/en not_active IP Right Cessation
- 1988-10-28 HU HU885630A patent/HU202824B/en not_active IP Right Cessation
-
1993
- 1993-02-11 GR GR920402546T patent/GR3007027T3/el unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1013907A (en) * | 1962-09-13 | 1965-12-22 | Ici Ltd | Alkene derivatives |
| US4536516A (en) * | 1962-09-13 | 1985-08-20 | Imperial Chemical Industries Plc | Alkene derivatives |
| EP0127128A1 (en) * | 1983-05-24 | 1984-12-05 | Bristol-Myers Company | Process for the conversion of the E isomer of 1,2-diphenyl-1-(4-(2-dimethylaminoethoxy)-phenyl)-1-butene to tamoxifen HCl |
Non-Patent Citations (6)
| Title |
|---|
| Acta Chimica Academine Scientiarum Hungavicae, "Synthesis and Structure Determination of Geometric Isomers of 1-Aryl-2-Ethyl-1,2-Diphenylethylenes by 1 H-NMR Spectroscopy", pp. 69-74 (1979). |
| Acta Chimica Academine Scientiarum Hungavicae, Synthesis and Structure Determination of Geometric Isomers of 1 Aryl 2 Ethyl 1,2 Diphenylethylenes by 1 H NMR Spectroscopy , pp. 69 74 (1979). * |
| Journal of Chromatography, "Separation of Tamoxifen Geometric Isomers & Metabolites by Bonded-Phase B-Cyclodextrin Chromatography", Armstrong et al., vol. 414 (1987), pp. 192-196. |
| Journal of Chromatography, Separation of Tamoxifen Geometric Isomers & Metabolites by Bonded Phase B Cyclodextrin Chromatography , Armstrong et al., vol. 414 (1987), pp. 192 196. * |
| Robertson et al. "Synthesis of E and Z Isomers of the Antiestrogen Tamoxifen, etc.", J. Org. Chem 47 2387-2393 (1982). |
| Robertson et al. Synthesis of E and Z Isomers of the Antiestrogen Tamoxifen, etc. , J. Org. Chem 47 2387 2393 (1982). * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5565611A (en) * | 1993-10-25 | 1996-10-15 | Taiho Pharmaceutical Co., Ltd. | Process for preparing acid addition salt of Z-isomer of triphenylethylene compound |
| US5693863A (en) * | 1994-01-03 | 1997-12-02 | Klinge Pharma Gmbh | Method for the production of E-1- 4'- (2- Dimethylaminoethoxy) - Phenyl!-1-(3-Hydroxyphenyl) -2-Phenyl-1-Butene |
| US5681835A (en) * | 1994-04-25 | 1997-10-28 | Glaxo Wellcome Inc. | Non-steroidal ligands for the estrogen receptor |
| US5877219A (en) * | 1994-04-25 | 1999-03-02 | Glaxo Wellcomeinc. | Non-steroidal ligands for the estrogen receptor |
| US7307102B2 (en) | 1997-08-15 | 2007-12-11 | Duke University | Method of preventing or treating estrogen-dependent diseases and disorders |
| CN114133334A (en) * | 2021-11-09 | 2022-03-04 | 北京京丰制药(山东)有限公司 | Industrial preparation process of tamoxifen citrate |
Also Published As
| Publication number | Publication date |
|---|---|
| NO884800D0 (en) | 1988-10-27 |
| FI884461A (en) | 1989-04-30 |
| HUT51592A (en) | 1990-05-28 |
| EP0313799A2 (en) | 1989-05-03 |
| HU202824B (en) | 1991-04-29 |
| DE3878394D1 (en) | 1993-03-25 |
| DK604288A (en) | 1989-04-30 |
| DK170300B1 (en) | 1995-07-31 |
| ES2038263T3 (en) | 1993-07-16 |
| DK604288D0 (en) | 1988-10-28 |
| FI884461A0 (en) | 1988-09-28 |
| FI94625C (en) | 1995-10-10 |
| FI94625B (en) | 1995-06-30 |
| EP0313799A3 (en) | 1990-05-30 |
| NO169120C (en) | 1992-05-13 |
| GR3007027T3 (en) | 1993-07-30 |
| EP0313799B1 (en) | 1993-02-10 |
| NO169120B (en) | 1992-02-03 |
| ATE85605T1 (en) | 1993-02-15 |
| NO884800L (en) | 1989-05-02 |
| DE3736682A1 (en) | 1989-05-11 |
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